Rekker’s fragmental method

Takeuchi, K., Kuroda, C. and Ishida, M. (1990). Prolog-Based Functional Group Perception and Calculation of 1-Octanol/Water Partition Coefficients Using Rekker s Fragment Method. J.Chem.Inf.Comput.ScL, 30,22-26. 

Comments on Rekker s Fragmental Method Although empirically useful, Rekker s assumption is an oversimplification because it depends only on the topological distance between two polar groups (i.e., on the number of carbon atoms that separate them), not on the nature of the polar groups. Indeed, it is difficult to understand how different polar groups (which may be halogens, H-bond acceptors, or H-bond donors) could elicit identical proximity effects. A simple molecular explanation for such proximity effects is to... 

In our opinion, Rekker s fragmental method is well suited to identifying intramolecular factors that influence lipophilicity, but it is not easily applicable to black-box computerized approaches. 

A variety of indirect methods have been developed to estimate Kow (Table 5). These include simple PPRs and SPRs (Fig. 5), as well as group additivity methods in which the lipophilic contributions of molecular fragments have been estimated (e.g., Rekker s fragment technique and UNIFAC). The existence of so many methods to estimate Kow suggests there are some fundamental difficulties in accurately determining this important parameter. As a minimum, we can expect that there will be differences in the values of a compound s Kow determined by the different techniques. This is the case, and a large literature has arisen on this subject (Andren et al., 1987 Sabljic, 1987 Eadsworth, 1986 De Voogt et al., 1988 Veith et al., 1979). 

Changes in temperature of, say, 5°C, have little effect on a partition coefficient. When log P is above 4, the shaking method has little reliability and recourse must be made to chromatography, or to calculation from Rekker s fragmental constants (see below). 

The measurement of the solubility of drugs in polar and non-polar media is very important in the pharmaceutical field. One method proposed to describe this solubility is the partition coefficient between octanol and water. The mathematical calculation of an octanol-water partition coefficient from values for functional groups was first proposed by Hansch et al. as Hansch s n constants,1 and was later developed by Rekker as hydrophobic fragmental constants (logP).2 This method was further improved by the use of molecular connectivities.17 The prediction of logP values can be performed by either a computer program or by manual calculation. For example, approximate partition coefficients (log P) have been calculated by Rekker s method ... 

Although the magic constant bears an unfortunate name, Rekker suggested that it originates from a fundamental property of water in the first solvation shell, namely a so-called quantum displacement of water molecules. A discussion of the relevance of the magic constant along with the related hydration factor, co, proposed by van de Waterbeemd and Testa, is outside the scope of this chapter. Table 3 summarizes the correction factors used in Rek-ker s revised fragmental method." ... 

In contrast to Rekker s method, CLOGP uses a set of simple rules to break the molecular structure into fragments. Thus a fragmentation scheme is always unique and is not left to arbitrary decisions. 

Chitosan which have the degree of the substitution of amino group, 0.85 (sample I) and 0.77 (sample II) (Kyowa Yushi Co. Ltd.) were used. The chitosan flakes were dissolved in 10% acetic acid and methanol and acylated by the carboxylic anhydride. The gel formed was washed with water and neutralized with O.IN KOH. Finally the products were washed with water and dried. A gel particles obtained were of diameter 50 to 300 Urn.5 6 The carboxylic anhydrides used were octanoic, dodecanoic and octa-decanoic derivatives. The chitosan gels obtained are shown in Figure 1. Figure 2 shows the variety of chemical structures for the dyes and the amino acids used, respectively. All of the dyes were prepared by the conventional methods, or purchased from Tokyo Kasei Co. D,L-amino acids were obtained from Nakarai Chemicals Co. The figures in the parentheses indicate Rekker s hydrophobic fragmental constant, Ef. ... 

Two different sets of fragment constants, f, for pathway 2 have been reported, one by Hansch and Leo [14] (Leo s method) and one by Xys and Rekker [33,34,39]. A detailed analysis and comparison of the two methods have not been made, but the method of Hansch and Leo [14] appears to be... 

---